Enhanced effects of co-administered dexamethasone and diclofenac on inflammatory pain processing and associated spinal c-Fos expression in the rat

Abstract 

This study determines the effects of dexamethasone versus co-administered dexamethasone and diclofenac, on carrageenan-evoked spinal c-Fos expression and peripheral oedema in the freely moving rat. Drugs were administered intravenously 25 min before intraplantar injection of carrageenan (6 mg/150 μ1 of saline). Three hours later the number of spinal c-Fos-LI neurones and peripheral oedema were assessed.

The total number of control carrageenan-evoked c-Fos-LI neurones in the lumbar spinal cord was 121 ± 5 labelled neurones per section, segments L4-L5, which were predominantly located in the superficial and deep laminae (41 ± 3% and 40 ± 2% of the total number of c-Fos-LI neurones per section, respectively) of the dorsal horn of the spinal cord. Pre-administered dexamethasone (0.05, 0.10 and 0.50 mg/kg i.v.) dose-dependently reduced the total number of c-Fos-LI neurones (30 ± 4%, 52 ± 3% and 58 ± 2% reduction, respectively), with effects of the higher doses being strongest on the deep laminae c-Fos-LI neurones. The effects of dexamethasone on the total number of c-Fos-LI neurones and the peripheral oedema were positively correlated. Co-administration of low doses of dexamethasone and diclofenac (0.025 + 1.5 mg/ kg i.v. respectively), which had negligible effects when administered separately, greatly reduced both the total number of carrageenan-evoked c-Fos-LI neurones (61 ± 5% reduction as compared to control value) and the peripheral oedema (80 ± 8% and 60 ± 5% reduction for ankle and paw oedema, respectively). The attenuation by co-administered dexamethasone and diclofenac, of both c-Fos expression and the peripheral oedema, was significantly greater than the effect of dexamethasone alone (P < 0.001 for both) and diclofenace alone (P < 0.001 for both).

Our study illustrates enhanced attenuating effects of co-administered dexamethasone and diclofenac on both inflammatory oedema and the associated spinal expression of c-Fos, an indicator of nociceptive transmission at the spinal level. The apparent interactions between the mechanisms of action of NSAIDs and steroids suggest that co-therapy may produce beneficial inflammatory and pain relief in the absence of excessive side effects.

Keywords:  Carrageenan, c-Fos, Dexamethasone, Diclofenac, Inflammatory pain, Spinal cord, (Rat)

Abbreviations:  ANOVA, analysis of variance, c-Fos-LI, c-Fos protein-like immunoreactivity, c-Fos protein-like immunoreactive, COX, cyclo-oxygenase, Fisher's PLSD test, Fisher's protected least-squares difference test, NSAIDs, non-steroid anti-inflammatory drugs, PBS, phosphate-buffered saline, PB, phosphate buffer

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